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Molecular Physiology & Biophysics

Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.

AUTHORS

Babon JA , DeNicola ME , Blodgett DM , Crèvecoeur I , Buttrick TS , Maehr R , Bottino R , Naji A , Kaddis J , Elyaman W , James EA , Haliyur R , Brissova M , Overbergh L , Mathieu C , Delong T , Haskins K , Pugliese A , Campbell-Thompson M , Mathews C , Atkinson MA , Powers AC , Harlan DM , Kent SC , . Nature medicine. 2016 12 ; 22(12). 1482-1487

ABSTRACT

A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood-derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis, the identification of autoreactive CD8(+) T cells in situ, in islets of human leukocyte antigen (HLA)-A2(+) donors and isolation and identification of DQ8 and DQ2-DQ8 heterodimer-restricted, proinsulin-reactive CD4(+) T cells grown from islets of a single donor with T1D. Here we present an analysis of 50 of a total of 236 CD4(+) and CD8(+) T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.

A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood-derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis, the identification of autoreactive CD8(+) T cells in situ, in islets of human leukocyte antigen (HLA)-A2(+) donors and isolation and identification of DQ8 and DQ2-DQ8 heterodimer-restricted, proinsulin-reactive CD4(+) T cells grown from islets of a single donor with T1D. Here we present an analysis of 50 of a total of 236 CD4(+) and CD8(+) T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.

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